KIT (also called CD117) is a receptor tyrosine
kinase (RTK) expressed on a wide variety of
cell types. The ligand for KIT is stem cell factor (SCF). The binding of SCF to the
extracellular domain of KIT induces receptor
dimerization and activation of downstream
signaling pathways, including the
PI3K-AKT-mTOR pathway, the RAS-RAF-MEK-ERK pathway, and the signal transducer and activator of
transcription 3 (acute-phase response factor),
or STAT3, pathway, all of which are involved in mediating pro-growth and pro-survival signals
within the cell (Figure 1).
Mutant KIT has been implicated in the pathogenesis of several cancers including melanoma, acute
leukemia, and gastrointestinal stromal tumor (GIST; Heinrich et al.
2003; Hirota et al.
The discovery of KIT mutations revolutionized
the treatment of GISTs. The use of imatinib mesylate (Gleevec), an oral KIT inhibitor leads to
rapid, substantial, and durable tumor responses (Demetri et al.
2002). Not all KIT mutations are associated with equal sensitivity to imatinib (Heinrich et al.
2008); some are more sensitive to second-generation KIT inhibitors.
Figure 1. Schematic of KIT signaling pathways. The binding of SCF, to the
KIT receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK), the PI3K pathway
(PI3K-AKT-mTOR), and the STAT3 pathway. The letter "K" within the schema denotes the tyrosine
Suggested Citation: Lovly, C., J. Sosman, W. Pao. 2015. KIT. My Cancer
(Updated December 7).
Last Updated: December 7, 2015
KIT in Melanoma
Somatic mutations in KIT have been found in 2–8%
(Beadling et al. 2008;
Curtin et al. 2006; Handolias et al.
et al. 2005) of all malignant melanoma. KIT mutations may be found in all melanoma
subtypes but are the most common in acral melanomas (10–20%) and mucosal melanomas (15–20%;
Beadling et al. 2008;
Curtin et al. 2006; Satzger et al.
et al. 2009). Among mucosal melanomas, KIT mutations are more common in anorectal and
vulvo-vaginal primaries (15–25%) than in sinonasal/oropharyngeal tumors (~7%).
Somatic point mutations in melanoma tumor
specimens have been detected predominantly in the juxtamembrane domain but also in the kinase domain of KIT. They can induce
ligand-independent receptor dimerization, constitutive kinase activity, and transformation (Growney et al.
2005; Hirota et al.
1998; Hirota et
al. 2001; Kitayama
et al. 1995). The spectrum of mutations overlaps with those found in gastrointestinal
stromal tumor (GIST).
An increasing number of case reports, retrospective studies, and phase II clinical trials have
demonstrated clinical responses of KIT mutated melanoma to imatinib (Carvajal et al.
2011; Guo et
al. 2011; Hodi et
al. 2013), sunitinib (Minor et al.
et al. 2009), sorafenib (Quintas-Cardama et al. 2008), and
nilotinib (Lebbe et al. 2014). In one case study, a patient with melanoma
harboring a KIT L576P mutation demonstrated a
response to everolimus after acquiring resistance to imatinib (Si et al. 2012).
In the majority of cases, KIT mutations are
non-overlapping with other oncogenic mutations
found in melanoma (e.g., NRAS mutations, BRAF
mutations, etc.; Beadling et al.
2008). In addition, in rare cases the KIT genotype of a primary lesion may differ from
its metastases (Terheyden
et al. 2010).
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. KIT in Melanoma. My
Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/kit/
(Updated June 18).
Last Updated: June 18, 2015
KIT Amplification in Melanoma
|Location of mutation
|Frequency of KIT amplification in melanomas arising from chronic sun damage
Frequency of KIT amplification in acral melanomas
Frequency of KIT
amplification in mucosal melanomas
|10% (Carvajal et
9.6% (Carvajal et al. 2011)
15.4% (Carvajal et al.
|Implications for Targeted Therapeutics
|Response to nilotinib
||Unknown at this timea
|Response to imatinib
||Confers decreased sensitivityb
|Response to sunitinib
||Unknown at this time
|Response to sorafenib
||Unknown at this time
a In a phase II clinical trial, while 5 of 26 patients with melanoma
harboring KIT mutations responded to
nilotinib, none of the 8 patients with melanoma with KIT amplification responded (Lebbe et al. 2014).
b In a phase II trial of imatinib in 25 patients with mucosal melanoma, acral
melanoma, and melanoma arising from chronic sun damage harboring KIT mutations or amplification, disease control rates were
correlated positively with KIT mutations but
not KIT amplification. Four patients with NRAS-mutated melanoma did not show response to
imatinib, suggesting that this is a mechanism of resistance (Hodi et al. 2013).
NOTE: OS = overall survival; PFS = progression-free survival; TTP = time to progression.
Suggested Citation: Lovly, C., D. Johnson, M. Sos. 2015. KIT Amplification in
Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/kit/338/
(Updated June 16).
Last Updated: June 16, 2015
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